Complex movement disorders (CMDs), defined as disorders in which patients are affected by more than one movement disorder (such as parkinsonism and dystonia, or myoclonus and tremor), are a continuing challenge for diagnosis and treatment. CMDs are usually progressive, prevent patients from performing basic daily functions such as walking, eating, and talking, and result in high disease-associated financial and personal burden for patients and their families. Moreover, the already-known phenotypic and etiologic heterogeneity associated with movement disorder genes is quite striking and presents a significant challenge for treatment. Therefore, early diagnosis is crucial for appropriate treatment to restore motor activities and improve patients' quality of life. Since genetic studies in movement disorders (MDs) have demonstrated their success in the discovery of underlying pathologic processes and have helped researchers to understand both disease manifestation and progression, the identification of genetic factors underlying, or contributing to, the development of MDs provides a powerful tool for understanding their associated pathology. Accordingly, in an attempt to identify molecular networks associated with these CMDs and to facilitate novel treatments, this proposal focuses on the recruitment of familial and sporadic patients with CMDs, and the identification of their disease-causing alleles. Because whole exome sequencing (WES) has proved its ability to identify causative alleles for inherited diseases, even in families previously deemed statistically underpowered for positional cloning, and has become a fruitful strategy for gene identification in both Mendelian and more complex traits, WES, along with SNP-based arrays, which will reduce the search for causal variants, will be used for disease- causing mutation identification in this proposal. We believe that intense study of these disorders represents a powerful approach to elucidate disease mechanism for both CMDs and for more common disorders such as Parkinson's disease, and will lead to improvements in both diagnoses and treatments. In conclusion, this study will contribute enormously to the identification of novel CMD genes and the characterization of their phenotype, which not only are essential for understanding the etiology and pathophysiology of CMDs, but also for developing more targeted and efficient therapeutic strategies that will be of great benefit to human health.